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bioRxiv · 10.1101/2020.11.05.370080

Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

Roberts, J. P.·Stokoe, S. A.·Sathler, M. F.·Nichols, R. A.·Kim, S.
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Abstract

Beta-amyloid (A{beta}) has been recognized as an early trigger in the pathogenesis of Alzheimers disease (AD) leading to synaptic and cognitive impairments. A{beta} can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), contributing to synaptic dysfunction in AD. The three major nAChR subtypes in the hippocampus are composed of 7-, 4{beta}2-, and 3{beta}4-nAChRs. A{beta} selectively affects 7- and 4{beta}2-nAChRs, but not 3{beta}4-nAChRs in hippocampal neurons, resulting in neuronal hyperexcitation. However, how nAChR subtype selectivity for A{beta} affects synaptic function in AD is not completely understood. Here, we showed that A{beta} associated with 7- and 4-containing nAChRs but not 3-containing receptors. Computational modeling suggested two amino acids in 7-nAChRs, Arginine 208 and Glutamate 211, were important for the interaction between A{beta} and 7-containing nAChRs. These residues were found to be conserved only in the 7 and 4 subunits. We therefore mutated these amino acids in 7-containing nAChRs to mimic the 3 subunit and found that mutant 7-containing receptors were unable to interact with A{beta}, providing direct molecular evidence for how A{beta} selectively interacted with 7- and 4-containing receptors, but not 3-containing nAChRs. Selective co-activation of 7- and 4{beta}2-nAChRs was also sufficient to reverse A{beta}-induced AMPA receptor (AMPAR) dysfunction, including A{beta}-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, the A{beta}-induced disruption of long-term potentiation was reversed by co-stimulation of 7- and 4{beta}2-nAChRs. These findings support a novel mechanism for A{beta}s impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.

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Roberts, J. P., Stokoe, S. A., Sathler, M. F., Nichols, R. A., Kim, S.. 2020-11-06. Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction. https://doi.org/10.1101/2020.11.05.370080

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